tbuckley/cabot-search huggingface dataset:
308 Tralokinumab provides other clinically meaningful improvements in adolescents with moderate-to-severe atopic dermatitis who did not achieve IGA 0/1 at week 16
Authors: Amy Paller, Andrew Blauvelt, Weily Soong, Chih-ho Hong, Marie L A Schuttelaar, Shannon  Schneider, Marie Holst Moerch, Eric  Simpson
Journal: British Journal of Dermatology (2023)

Abstract In the monotherapy phase 3 trial (ECZTRA 6, NCT03526861) in adolescents with moderate-to-severe atopic dermatitis (AD) treated with tralokinumab, IGA of clear/almost clear skin (IGA 0/1) at week 16 was a primary endpoint. IGA 0/1 can be a high standard to achieve for patients with moderate-to-severe AD and may not fully reflect achievement of other clinically meaningful parameters, such as improvement in signs, symptoms and/or quality-of-life (QoL). To assess the impact of tralokinumab (150 or 300 mg) vs. placebo on other clinically meaningful parameters at week 16 in the subset of patients who did not achieve IGA 0/1 at week 16 and/or used rescue medication. Adolescents (12–17 years) were randomized to subcutaneous tralokinumab 150 or 300 mg, or placebo, every 2 weeks. Patients who did not achieve IGA 0/1 at week 16 and/or utilized rescue therapy were included in this post-hoc analysis. Non-responder imputation was used for patients who utilized rescue therapy or had missing data. Clinically meaningful responses were defined as EASI-50, ≥ 3-point improvement in pruritus NRS, or ≥6-point improvement in CDLQI. At week 16, 78.6% and 82.5% of tralokinumab-treated patients (150 mg/300 mg) vs. 95.7% (placebo) exhibited IGA &amp;gt; 1 and/or used rescue therapy. 36.4% (150 mg) and 52.5% (300 mg) of patients with IGA &amp;gt; 1 in the tralokinumab arms, compared to 21.1% (placebo), achieved clinically meaningful responses in at least one measure: EASI-50, pruritus NRS, or CDLQI. Greater proportions of tralokinumab-treated patients (150/300 mg vs. placebo) achieved EASI-50 (31.2%/41.3% vs. 10.0%) and ≥3-point improvement in pruritus NRS (21.6%/22.8% vs. 8.0%). A greater proportion of tralokinumab 300 mg patients vs. placebo (35.2% vs. 15.0%) achieved ≥6-point improvement in CDLQI. Many tralokinumab-treated adolescents who did not achieve IGA 0/1 at week 16 and/or used rescue therapy still achieved clinically meaningful improvements in AD signs, symptoms, and/or QoL.
287 Targeting the inhibitory receptor Siglec-8 on mast cells represents an attractive approach to reduce MRGPRX2-mediated mast cell activation
Authors: Zachary Benet, Alan Wong, Julia Schanin, Bradford A Youngblood
Journal: British Journal of Dermatology (2023)

Abstract Atopic dermatitis (AD) is a debilitating type 2 inflammatory disease of the skin characterized by pruritus. Mast cells (MCs) and eosinophils (eos) are elevated in AD tissue. Siglecs are inhibitory receptors found on immune cells, with Siglec-8 selectively expressed on MCs and eos. Engagement of Siglec-8 with antibody results in broad inhibition of MC activation (IgE-dependent and -independent pathways). MCs and eos are key drivers of itch. Crosstalk between skin MCs and sensory neurons contributes to non-histaminergic itch via activation of Mas-related G-protein receptor X2 (MRGPRX2). MRGPRX2-mediated MC activation has been implicated in chronic urticaria and allergic contact dermatitis, however, this mechanism has not been studied in the pathogenesis of AD. We hypothesize that activation of MCs through MRGPRX2 contributes to chronic inflammation and itch in patients with AD. Supernatants were collected from intact ex vivo cultured lesional and non-lesional skin biopsies from donor-matched patients with AD or healthy volunteers. Following ex vivo culture, secreted mediators were quantified using ELISA and meso-scale discovery (MSD). Biopsies were enzymatically digested and MRGPRX2 expression and function were measured using flow cytometry and MSD. Acute MRGPRX2 activation in vivo and the effects of a Siglec-8 monoclonal antibody (mAb), compared with isotype control, were studied in Siglec-8 transgenic mice. MC and eosinophil numbers were increased in lesional biopsies from patients with AD compared with patient-matched non-lesional and healthy volunteer control biopsies. MCs from AD lesional biopsies showed significant evidence of activation and degranulation compared to MCs in non-lesional biopsies. Levels of MC-specific proteases, inflammatory and pruritic mediators were significantly elevated in supernatants from ex vivo cultured lesional biopsies, including CPA3, CCL17 (TARC), IL-8, IL-13 and IL-31. Levels of MRPGRX2 ligands in supernatants from AD lesional biopsies were significantly elevated. Ex vivo challenge of healthy skin tissue with MRGPRX2 ligands partially replicated the AD lesional microenvironment. Lastly, intradermal injection of MRGPRX2 ligands in Siglec-8 transgenic mice induced inflammation and itch, which were inhibited with a Siglec-8 mAb. MRGPRX2-mediated MC activation contributes to inflammation in patients with AD through the release of chemotactic, proteolytic, pruritic and inflammatory factors. Therapeutic strategies that broadly target MCs, such as a lirentelimab (AK002) and a Siglec-8 mAb, may decrease the severity of AD.
347 The real-world burden of atopic dermatitis: MEASURE-AD multicountry study results from Brazil, Mexico and Argentina
Authors: Roberta Fachini Jardim Criado, Tatiane Rodrigues, Lucila de Campos, Tania Cestari, Jorge Maspero, Paula Carolina Luna, María Valeria Angles, Martti Antila
Journal: British Journal of Dermatology (2023)

Abstract The burden of atopic dermatitis (AD), a chronic, relapsing inflammatory skin disease, increases with disease severity and is associated with multiple flares per year over many years. We characterized the real-world burden of disease, including flares, in patients with AD enrolled in MEASURE-AD from Latin America. Patients (aged ≥12 years) with physician-confirmed AD receiving or eligible for systemic therapy were enrolled in MEASURE-AD between December 2019 and June 2020. Patient characteristics, treatments and outcomes were recorded during a single office visit. Primary outcome measures included worst itch within the past 24 h (Worst Pruritus Numerical Rating Scale [WP-NRS]) and quality of life (QoL; Dermatology Life Quality Index [DLQI] and cDLQI). Among secondary outcomes, the frequency and duration of disease flares within the last 6 months were assessed. Herein result from the Latin American (Brazil, Mexico and Argentina) population (N = 180; adults (≥18 years), n = 157; adolescents, n = 23). Analyses were based on observed data; only descriptive statistics were presented. The mean (SD) age was 33.8 (17.0) years, 52.2% were males and all patients were receiving AD treatment, including 65.6% receiving systemic therapy alone or in combination. Severe pruritus (WP-NRS ≥7) was reported by 54.4% of patients (adults, 57.3%; adolescents, 34.8%). A very or extremely large effect on QoL (DLQI or cDLQI ≥11) was reported among 50.0% of patients ≥16 years and 42.9% of patients 12–15 years. Over the previous 6 months, 0, 1–2, 3–4, 5–6 and &amp;gt;6 flares were reported by 8.3%, 27.2%, 31.1%, 11.7% and 15.6% of patients, respectively. On average, flares lasted 15.2 days (adults, 15.9 days; adolescents, 11.1 days). Although all patients received treatment and two-thirds received systemic therapies, severity scores and impact on QoL and itch were extremely high, suggesting that AD is not adequately controlled in all patients.
323 Onset of atopic comorbidities relative to atopic dermatitis diagnosis in a real-world setting using an Israeli claims database
Authors: Yael Leshem, Allan Becker, William W Busse, Lisa A Beck, Clara Weil, Moataz Daoud, Robert Lubwama
Journal: British Journal of Dermatology (2023)

Abstract Patients with atopic dermatitis (AD) are more likely than the general population to have other type 2 associated conditions, for example, asthma, allergic rhinitis (AR) and food allergy (FA).1,2 Classically, the atopic march is thought to begin with AD and progresses to FA, asthma and AR,1,2 but this may be an oversimplification. This study aimed to describe the epidemiology of type 2 associated conditions included in the atopic march among patients newly diagnosed with AD in a large healthcare provider database in Israel. This retrospective cohort study was performed using the Maccabi Healthcare Services database in Israel, which includes over 2.5 million members. Based on the International Classification of Diseases, 9th revision (ICD-9) diagnosis codes, patients with diagnosed AD during 2000–2019 were identified. The earliest AD diagnosis was defined as the index date and patients had to have been enrolled for ≥12 months pre-index to exclude prevalent AD. Diagnosis data were obtained during 1998–2020 to describe the cumulative prevalence of asthma, AR and FA pre- and post-AD diagnosis (−1, 0, 1, 5, 10 and 20 years) using Kaplan–Meier analysis among patients aged &amp;lt;3, 3–5, 6–11, 12–17 and ≥18 years at AD diagnosis. The study included 243,687 patients (51.6% female) with AD. The median (interquartile range) age at AD diagnosis was 4.3 (1.1–22.8) years, with 43.9% and 72.7% of patients diagnosed before age 3 and 18 years, respectively. At AD diagnosis, 28.1% had a prior/concurrent diagnosis of asthma/AR/FA (asthma: 17.1%, AR: 12.8%, FA: 3.4%). Among patients diagnosed with AD at age &amp;lt;3 years, 16.2% had been diagnosed with asthma/AR/FA by/at the time of their AD diagnosis (asthma: 10.6%, AR: 2.2%, FA: 4.9%). In this youngest age group, the cumulative prevalences of asthma/AR/FA were 28.8%, 42.7%, 49.6% and 59.6% within 1, 5, 10 and 20 years post-AD diagnosis. Among patients diagnosed with AD in adulthood, 37.7% had been diagnosed with asthma/AR/FA by/at the time they were diagnosed with AD (asthma: 16.5%, AR: 29.7%, FA: 0.8%). It this oldest age group, the cumulative prevalences of asthma/AR/FA were 40.3%, 46.1%, 50.9% and 57.6% within 1, 5, 10 and 20 years post-AD diagnosis. The results of this real-world analysis are consistent with previous evidence that AD is primarily a childhood-onset disease. The sharpest increase in type 2 associated conditions was seen in the 5 years post-AD diagnosis among patients diagnosed with AD at age &amp;lt;3 years. Most adults newly diagnosed with AD who developed another type 2 associated condition had already done so prior to AD diagnosis, although it is possible that earlier AD diagnoses were not captured. Regardless of age at AD diagnosis, nearly 60% of patients with AD were estimated to have ≥1 of asthma/AR/FA within 20 years of their AD diagnosis.
341 Dupilumab improves itch and skin lesions in adults with prurigo nodularis regardless of prior use of immunosuppressants or phototherapy: post-hoc results from PRIME and PRIME2 clinical trials
Authors: Shawn G Kwatra, Gil Yosipovitch, Sonja  Ständer, Brian S Kim, Jérôme Msihid, Ashish Bansal, Renata Martinčová, Simmi  Wiggins, Noah A Levit, Ryan B Thomas, Donia Bahloul
Journal: British Journal of Dermatology (2023)

Abstract Dupilumab is the only FDA-approved systemic therapy for prurigo nodularis (PN), however, immunosuppressants (IS) and phototherapy have been used off-label for the treatment of this condition. Patients with prior IS/phototherapy treatment may represent a more severe and/or treatment-refractory population of patients with PN. Report post-hoc efficacy of dupilumab in patients with PN, with or without prior use of IS or phototherapy for PN. LIBERTY-PN PRIME and PRIME2 (NCT04183335 and NCT04202679) are randomized, 24-week, phase 3 studies in adults with PN that is inadequately controlled by topical prescription therapies or for whom those therapies are not advisable. Primary outcomes included a ≥4-point improvement in the weekly average of Worst Itch Numerical Rating Scale (WI-NRS) from baseline to week 24, and an Investigator’s Global Assessment for PN stage (IGA PN-S) score of 0/1 (clear/almost clear) at week 24. Safety outcomes included the incidence of treatment-emergent adverse events (TEAEs). Among patients with PN, 8.0% reported prior use of phototherapy, and 36.7% reported prior use of IS; overall, 126 (dupilumab group, n = 62; placebo group, n = 64) patients with and 185 (dupilumab, n = 91; placebo, n = 94) patients without prior IS/phototherapy use were included. A larger proportion of patients with prior treatment vs. patients without prior treatment had severe disease, as measured by IGA PN-S (40.5% vs. 29.0%). The baseline WI-NRS score (SD) for overall patients with prior treatment was 8.6 (1.0) and for patients without prior treatment was 8.4 (1.0). At week 24, 67.7% vs. 15.6% of patients in the dupilumab vs. placebo groups with prior treatment (odds ratio [95% confidence interval]: 13.6 [3.7–49.7]; P &amp;lt; 0.0001), and 52.7% vs. 21.3% of patients without prior treatment (5.8 [2.4–14.0]; P &amp;lt; 0.0001) achieved improvement in WI-NRS. Similarly, 35.5% vs. 10.9% (3.1 [1.2–8.4]; P = 0.0162) of patients with and 53.8% vs. 21.3% (5.0 [2.3–10.8]; P &amp;lt; 0.0001) of those without prior treatment achieved IGA PN-S score of 0/1, respectively. TEAEs were reported by 43 (69.4%) vs. 34 (53.1%) patients (dupilumab vs. placebo groups) with and 54 (60.0%) vs. 55 (59.1%) without prior treatment, respectively. Patients treated with dupilumab experienced a greater and clinically meaningful improvement in itch and achieved skin that was clear/almost clear of nodules at week 24, regardless of prior use of IS/phototherapy for the treatment of PN. The incidence of TEAEs was generally consistent among patients with and without prior IS/phototherapy.
Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria
Authors: Maureen Ty, Shenghuan Sun, Perri C. Callaway, John Rek, Kathleen D. Press, Kattria van der Ploeg, Jason Nideffer, Zicheng Hu, Sandy Klemm, William Greenleaf, Michele Donato, Stephen Tukwasibwe, Emmanuel Arinaitwe, Felistas Nankya, Kenneth Musinguzi, Dean Andrew, Lauren de la Parte, Diego Martinez Mori, Savannah N. Lewis, Saki Takahashi, Isabel Rodriguez-Barraquer, Bryan Greenhouse, Catherine Blish, PJ Utz, Purvesh Khatri, Grant Dorsey, Moses Kamya, Michelle Boyle, Margaret Feeney, Isaac Ssewanyana, Prasanna Jagannathan
Journal: Science Translational Medicine (2023)

Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56 neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56 dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56 neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56 dim NK cells. Higher frequencies of CD56 neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.
Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma
Authors: Subhajit Ghosh, Jiayi Huang, Matthew Inkman, Jin Zhang, Sukrutha Thotala, Ekaterina Tikhonova, Natalia Miheecheva, Felix Frenkel, Ravshan Ataullakhanov, Xiaowei Wang, David DeNardo, Dennis Hallahan, Dinesh Thotala
Journal: Science Translational Medicine (2023)

Severe and prolonged lymphopenia frequently occurs in patients with glioblastoma after standard chemoradiotherapy and has been associated with worse survival, but its underlying biological mechanism is not well understood. To address this, we performed a correlative study in which we collected and analyzed peripheral blood of patients with glioblastoma (
Site-Specific Fracture Incidence Rates Among Patients With Type 1 Diabetes, Type 2 Diabetes, or Without Diabetes in Denmark (1997–2017)
Authors: Annika Vestergaard Kvist, Mohamad I. Nasser, Peter Vestergaard, Morten Frost, Andrea M. Burden
Journal: Diabetes Care (2023)

OBJECTIVE To investigate trends in incidence rates (IRs) at various fracture sites for patients with type 1 diabetes and type 2 diabetes compared with patients without diabetes in Denmark in 1997–2017. RESEARCH DESIGN AND METHODS Patients aged ≥18 years with a vertebral, hip, humerus, forearm, foot, or ankle fracture between 1997 and 2017 were identified from Danish hospital discharge data. IRs per 10,000 person-years were calculated over the study period. Median IRs for the first (1997–2001) and the last (2013–2017) 5 years were compared. We used Poisson models to estimate age-adjusted IR ratios (IRRs) of fractures among patients with type 1 and type 2 diabetes versus patients without diabetes. RESULTS Except for foot fractures, fracture IRs were higher in patients with type 1 or type 2 diabetes compared with patients without diabetes. Hip fracture IRs declined between the first and last 5 years by 35.2%, 47.0%, and 23.4% among patients with type 1, type 2, and without diabetes, respectively. By contrast, vertebral fracture IRs increased 14.8%, 18.5%, 38.9%, respectively. While age-adjusted IRRs remained elevated in patients with type 1 diabetes compared with patients without diabetes, IRRs in patients with type 2 diabetes converged with those observed in patients without diabetes. CONCLUSIONS Unadjusted fracture rates are higher in patients with diabetes but have decreased between 1997 and 2017 except for vertebral fractures, which increased in all groups. Fracture rates change after age adjustment.
SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common<i>ALDH2</i>alcohol flushing variant
Authors: Hongchao Guo, Xuan Yu, Yu Liu, David T. Paik, Johanne Marie Justesen, Mark Chandy, James W. S. Jahng, Tiejun Zhang, Weijun Wu, Freeborn Rwere, Shane Rui Zhao, Suman Pokhrel, Rabindra V. Shivnaraine, Souhrid Mukherjee, Daniel J. Simon, Amit Manhas, Angela Zhang, Che-Hong Chen, Manuel A. Rivas, Eric R. Gross, Daria Mochly-Rosen, Joseph C. Wu
Journal: Science Translational Medicine (2023)

The common aldehyde dehydrogenase 2 ( ALDH2 ) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world’s population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell–derived ECs (iPSC-ECs) and CRISPR-Cas9–corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2 -induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2 -associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2 -mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na + /H + -exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2 -induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.
A Prospective Analysis of the Immunogenicity of Cryopreserved Nonvalved Allografts Used in Pediatric Heart Surgery
Authors: John P. Breinholt, John A. Hawkins, Linda M. Lambert, Thomas C. Fuller, Tracie Profaizer, Robert E. Shaddy
Journal: Circulation (2000)

Background —The purpose of this study was to prospectively determine the immunogenicity of nonvalved allograft tissue used to repair congenital heart defects. Methods and Results —We prospectively analyzed the immune response of 11 children, 1.4 months to 10 years of age, who required nonvalved allografts to alleviate stenosis during repair of congenital heart defects. In 7 patients, pulmonary arterial grafts were used; in 3 patients, monocusp pulmonary artery grafts were used; and in 1 patient, a section of glutaraldehyde-preserved allograft pericardium was used. We measured the level of HLA panel-reactive antibody (PRA) before surgery, 1 week after, 1 month after, and 3 months after surgery. PRA was determined by the antiglobulin technique and flow cytometry. HLA class I and class II antibodies measured by either technique were negligible before and 1 week after surgery. Nine of 11 patients (82%) exhibited a significant immune response at 1 month after surgery that further increased at 3 months. The measured PRA for class I antibodies with the antiglobulin technique increased to 43±36% at 1 month and to 69±38% at 3 months after surgery. Flow cytometry class I PRA measurements were similar. Class II PRA increased to 26±34% at 1 month and to 41±36% at 3 months. Age negatively correlated with the degree of elevation of PRA, but neither allograft area nor the area indexed to patient body surface area correlated with PRA. Conclusions —Cryopreserved nonvalved allografts induce a strong HLA antibody response in the majority of children.